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Broad and Differential Animal ACE2 Receptor Usage by SARS-Cov-2

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Broad and Differential Animal ACE2 Receptor Usage by SARS-Cov-2 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.19.048710; this version posted April 19, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Broad and differential animal ACE2 receptor usage by SARS-CoV-2 2 3 Xuesen Zhao1, 2#*, Danying Chen1, 2#, Robert Szabla3, Mei Zheng1, 2, Guoli Li1, 2, 4 Pengcheng Du1, 2, Shuangli Zheng1, 2, Xinglin Li1, 2, Chuan Song1, 2, Rui Li1, 2, Ju-Tao 5 Guo4, Murray Junop3, Hui Zeng1, 2*, Hanxin Lin5* 6 1Institute of Infectious disease, Beijing Ditan Hospital, Capital Medical University, 7 Beijing 100015, China. 8 2Beijing Key Laboratory of Emerging Infectious Disease, Beijing 100015, China. 9 3Department of Biochemistry, Western University, 1151 Richmond Street, London, 10 Ontario, Canada. 11 4Baruch S. Blumberg Institute, Hepatitis B Foundation, 3805 Old Easton Road, 12 Doylestown, PA 18902. USA. 13 5Department of Pathology and Laboratory Medicine, Western University, 1151 14 Richmond Street, London, Ontario, Canada. 15 16 Running Title: Broad animal ACE2 receptor usage by SARS-CoV-2 17 18 * Corresponding author’s e-mail address: 19 Xuesen Zhao, [email protected] 20 Hui Zeng, [email protected] 21 Hanxin Lin, [email protected] 22 # These authors are co-first authors. 23 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.19.048710; this version posted April 19, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 24 ABSTRACT 25 The COVID-19 pandemic has caused an unprecedented global public health and 26 economy crisis. The origin and emergence of its causal agent, SARS-CoV-2, in the 27 human population remains mysterious, although bat and pangolin were proposed to be 28 the natural reservoirs. Strikingly, comparing to the SARS-CoV-2-like CoVs identified in 29 bats and pangolins, SARS-CoV-2 harbors a polybasic furin cleavage site in its spike (S) 30 glycoprotein. SARS-CoV-2 uses human ACE2 as its receptor to infect cells. Receptor 31 recognition by the S protein is the major determinant of host range, tissue tropism, and 32 pathogenesis of coronaviruses. In an effort to search for the potential intermediate or 33 amplifying animal hosts of SARS-CoV-2, we examined receptor activity of ACE2 from 34 14 mammal species and found that ACE2 from multiple species can support the 35 infectious entry of lentiviral particles pseudotyped with the wild-type or furin cleavage 36 site deficient S protein of SARS-CoV-2. ACE2 of human/rhesus monkey and rat/mouse 37 exhibited the highest and lowest receptor activity, respectively. Among the remaining 38 species, ACE2 from rabbit and pangolin strongly bound to the S1 subunit of 39 SARS-CoV-2 S protein and efficiently supported the pseudotyped virus infection. These 40 findings have important implications for understanding potential natural reservoirs, 41 zoonotic transmission, human-to-animal transmission, and use of animal models. 42 43 44 45 Key words: SARS-CoV-2; animal ACE2; receptor; entry; furin cleavage; animal hosts 46 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.19.048710; this version posted April 19, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 47 Introduction 48 49 Coronavirus disease 2019 (COVID-19) was first identified in Dec. 2019 in the city 50 of Wuhan, China 1, and has since spread worldwide, causing 2.3 million infected and 51 around 160,000 fatalities as of April 18th, 2020 (https://coronavirus.jhu.edu/map.html). 52 These numbers are still growing rapidly. The global COVID-19 pandemic has caused an 53 unprecedented public health and economy crisis. 54 COVID-19 is caused by a novel coronavirus, Severe Acute Respiratory Syndrome 55 Coronavirus 2 (SARS-CoV-2; initially named as 2019-nCoV) 2,3. The origin of 56 SARS-CoV-2 and its emergence in the human population remain mysterious. Many of 57 the early cases were linked to the Huanan seafood and wild animal market in Wuhan 58 city, raising the possibility of zoonotic origin 4. Sequencing analyses showed that the 59 genome of SARS-CoV-2 shares 79.5%, 89.1%, 93.3%, and 96.2% nucleotide sequence 60 identity with that of human SARS-CoV, bat coronavirus (CoV) ZC45, bat CoV 61 RmYN02, and bat CoV RaTG13, respectively, suggesting that SARS-CoV-2 probably 62 has bat origins 2,3,5. This finding is not surprising as bats are notorious for serving as the 63 natural reservoir for many emerging zoonotic viral pathogens, including two other 64 deadly human coronaviruses, SARS-CoV and Middle East respiratory syndrome 65 coronavirus (MERS-CoV), which caused global outbreak during 2002-2003 and 66 2012-2015, respectively 6,7. 67 Although SARS-CoV-2 may have originated from bats, bat CoVs are unlikely to 68 jump directly to humans due to the general ecological separation. Other mammal 69 species may have been served as intermediate or amplifying hosts where the progenitor 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.19.048710; this version posted April 19, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 70 virus acquires critical mutations for efficient zoonotic transmission to human. This has 71 been seen in the emergence of SARS-CoV and MERS-CoV where palm civet and 72 dromedary camel act as the respective intermediate host 7. The Huanan seafood and 73 wild animal market in Wuhan city would otherwise be a unique place to trace any 74 potential animal source; however, soon after the disease outbreak, the market was 75 closed and all the wild animals were cleared, making this task very challenging or even 76 impossible. As an alternative, wide screening of wild animals becomes imperative. 77 Several recent studies identified multiple SARS-COV-2-like CoVs (SL-CoVs) from 78 smuggled Malayan pangolins in China. These pangolin CoVs (PCoV) form two 79 phylogenetic lineages, PCoV-GX and PCoV-GD 8-11. In particular, lineage PCoV-GD 80 was found to carry a nearly identical receptor-binding motif (RBM) in the spike (S) 81 protein to that of SARS-CoV-2 (Fig.1). However, the genome of these pangolin 82 SL-CoVs share only 85.5%-92.4% nucleotide identities with that of SARS-CoV-2. This 83 is in contrast to SARS-CoV and MERS-CoV where CoVs isolated form the 84 intermediate host palm civet and dromedary camel share 99.6% and 99.9% % genome 85 sequence identities with their human counterpart, respectively 12,13. Therefore, pangolins 86 tested in these studies are not the direct intermediate host for SARS-CoV-2. Whether or 87 not SARS-CoV-2 came from other pangolins or other wild animal species remains to be 88 determined. 89 Receptor recognition by the viral S protein is the major determinant of host range, 90 cell, tissue tropism, and pathogenesis of coronaviruses 14. The S protein of 91 SARS-CoV-2 is a type I membrane glycoprotein, which can be cleaved to S1 and S2 92 subunit during biogenesis at the polybasic furin cleavage site (RRAR) (Fig.1) 15-17. 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.19.048710; this version posted April 19, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 93 Previous studies have shown that furin cleavage is not essential for coronavirus-cell 94 membrane fusion, but enhances cell-to-cell fusion 18-22, increases the fitness of sequence 95 variant within the quasispecies population of bovine CoV 23, and convert avirulent avian 96 influenza virus isolate to a highly pathogenic isolate 24. Interestingly, this cleavage site 97 is not present in the S protein of SARS-CoV, bat SL-CoVs or pangolin SL-CoVs 98 identified so far 5,15. During cell entry, S1 binds to the cellular receptor, subsequently 99 triggering a cascade of events leading to S2-mediated membrane fusion between host 100 cells and coronavirus particles 25. S1 protein contains an independently folded domain 101 called the receptor binding domain (RBD), which harbors an RBM that is primarily 102 involved in contact with receptor (Fig. 1). Human ACE2 (hACE2) has been identified as 103 the cellular receptor for both SARS-CoV-2 3,15,17,26 and SARS-CoV 27. In addition to 104 hACE2, ACE2 from horseshoe bat (Rhinolophus alcyone) was found to support cell 105 entry of SARS-CoV-2 S-mediated VSV-based pseudotyped virus 15. By using infectious 106 virus it has also been shown that ACE2 from Chinese horseshoe bat (Rhinolophus 107 sinicus), civet and swine, but not mouse, could serve as functional receptors 3. However, 108 in this infection system, the entry step was coupled with other steps during virus life 109 cycle, i.e.
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